Non-myeloablative approaches to hematopoietic cell transplantation (HCT) can potentially harness an immunotherapeutic graft-versus-tumor benefit while avoiding some of the severe toxicities associated with conventional, myeloablative HCT. Several clinical studies of non-myeloablative HCT have revealed a new and surprising phenomenon wherein loss of donor chimerism can sometimes be associated with sustained tumor regressions, even of advanced hematologic malignancies. We have developed a murine model in which to assess the mechanism of this phenomenon. We have demonstrated that alloresponses against donor antigens (either in association with spontaneous graft rejection or induced by infusion of non-tolerant host-type lymphocytes) lead to significant anti-tumor responses against recipient myeloid or lymphoid tumors. We now propose to optimize and determine the mechanisms underlying this phenomenon, which suggests a new strategy for achieving anti-tumor effects without augmenting the risk of GVHD. Specifically, we aim: 1) To determine the source and phenotype of cells mediating anti-tumor effects following recipient lymphocyte infusions (RLI) or spontaneous loss of chimerism; 2) To address the hypothesis that indirect presentation of alloantigens by recipient APC leads to the generation of tumor antigen-specific effector CTL and cytokine-producing cells in chimeras receiving RLI; 3) To utilize a TCR transgenic/model tumor antigen system to directly assess the hypothesis that RLI leads to a loss of tolerance among CD4+ and CD8+ cells that recognize tumor antigens; 4) To determine the mechanism by which IFN-gamma mediates anti-tumor effects in RLI recipients; 5) To evaluate strategies for optimizing the anti-tumor effect of RLI. Results of these studies will lead toward an understanding of the immunological events underlying the clinical phenomenon of tumor regression associated with rejection of donor marrow. Moreover, they will advance the development of a potential new strategy for achieving anti-tumor effects that is not associated with a risk of graft-versus-host disease, the major complication that currently limits the clinical success of non-myeloablative HCT.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Mccarthy, Susan A
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Massachusetts General Hospital
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Sykes, M (2015) Immune tolerance in recipients of combined haploidentical bone marrow and kidney transplantation. Bone Marrow Transplant 50 Suppl 2:S82-6
Li, Hao Wei; Sykes, Megan (2012) Emerging concepts in haematopoietic cell transplantation. Nat Rev Immunol 12:403-16
Flutter, Barry; Edwards, Noha; Fallah-Arani, Farnaz et al. (2010) Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation. J Clin Invest 120:3855-68
Saito, Toshiki I; Fujisaki, Joji; Carlson, Alicia L et al. (2010) Persistence of donor-derived protein in host myeloid cells after induced rejection of engrafted allogeneic bone marrow cells. Exp Hematol 38:333-9
Saito, Toshiki I; Li, Hao Wei; Sykes, Megan (2010) Invariant NKT cells are required for antitumor responses induced by host-versus-graft responses. J Immunol 185:2099-105
Sykes, Megan (2009) Mechanisms of transplantation tolerance in animals and humans. Transplantation 87:S67-9
Sykes, Megan (2009) Hematopoietic cell transplantation for tolerance induction: animal models to clinical trials. Transplantation 87:309-16
Chakraverty, Ronjon; Flutter, Barry; Fallah-Arani, Farnaz et al. (2008) The host environment regulates the function of CD8+ graft-versus-host-reactive effector cells. J Immunol 181:6820-8
Gibbons, Carrie; Sykes, Megan (2008) Manipulating the immune system for anti-tumor responses and transplant tolerance via mixed hematopoietic chimerism. Immunol Rev 223:334-60
Sykes, M (2007) Immune tolerance: mechanisms and application in clinical transplantation. J Intern Med 262:288-310

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